The U.S. Food and Drug Administration (FDA) has approved a new indication for Symbyax (olanzapine and fluoxetine HCl capsules), Eli Lilly and Company has announced.
Symbyax is now the first drug approved by the FDA for the acute treatment of treatment-resistant depression (TRD).
"Living with major depressive disorder is difficult and distressing for anyone, but even more so for patients whose symptoms continue despite treatment," said Lilly Medical Director Dr. Sara Corya. "Until today, there has been no approved medication for treatment-resistant depression. Now, after two failed attempts with other antidepressants, doctors and patients have a new treatment option."
In other actions, the FDA approved two new combination indications for Zyprexa (olanzapine) and fluoxetine for the acute treatment of bipolar depression and TRD. Lilly originally developed Prozac (fluoxetine HCl), the branded version of fluoxetine.
Additionally, the format of the product labels was updated according to the Physician's Labeling Rule (PLR), which many consider easier to understand. Additions were also made to the Medication Guides for Symbyax and Prozac, and a new Medication Guide was created for Zyprexa. Medication Guides include information for patients about potential risks associated with a particular product.
"Lilly maintains its commitment to patients by the continued research of Zyprexa, Symbyax, and Prozac," said Dr. Cherri Miner, Lilly neuroscience senior medical director. "Today's new indications confirm that these medications are valuable tools for patients in the fight against severe and disabling mental illness, and expand treatment options for prescribers and patients."
Indication Details:
- The new Symbyax TRD indication is for acute treatment of adult patients with major depressive disorder who have not responded to two separate trials of different antidepressants of adequate dose and duration in their current episode.
- Zyprexa, in combination with fluoxetine, is now approved for the acute treatment of TRD in adults.
- Symbyax was the first drug approved by the FDA for acute treatment of bipolar depression in adults in 2003. Zyprexa, in combination with fluoxetine, is now approved for the same indication.
With these FDA approvals, clinicians in the United States have the choice to use the single pill option (Symbyax), or the two drugs (Zyprexa and fluoxetine) together, allowing physicians to tailor treatment to each patient's needs. Neither Zyprexa nor fluoxetine are indicated as monotherapy for bipolar depression or TRD.
Additional Label Changes
In addition to the new indications, Lilly has updated the Symbyax and Zyprexa labels to include additional information regarding weight gain, hyperglycemia, and hyperlipidemia following the FDA's review of clinical trial data that Lilly submitted to the FDA between August 2007 and July 2008. In the course of this review, Lilly provided data from several large databases, including analyses of placebo-controlled data, comparator-controlled data, long-term data and special populations, including antipsychotic-naive patients.
Symbyax and Zyprexa in Combination with Fluoxetine Supportive Study Details for TRD
The data package submitted to the FDA supporting the approval of Symbyax for TRD as well as the approval of Zyprexa in combination with fluoxetine for TRD, included one pivotal trial and data from three supportive trials and one inconclusive trial. The TRD-related label language includes efficacy data from three of these clinical studies (n=579). Acute safety information was based on a total of 10 studies. Doses evaluated in these studies ranged from 6-18 mg for olanzapine and 25-50 mg for fluoxetine in fixed combination.
An eight-week randomized, double-blind, controlled study was conducted to evaluate the efficacy of Symbyax in patients (n=300) who met the fourth edition of "Diagnostic and Statistical Manual of Mental Disorders" (DSM-IV) criteria for major depressive disorder (MDD) and did not respond to two antidepressants of adequate dose and duration in their current episode. Patients who were not responding to an antidepressant in their current episode entered an eight-week open-label fluoxetine lead-in, and then non-responders were randomized (1:1:1) to receive an eight-week trial of Symbyax, olanzapine, or fluoxetine. Symbyax was flexibly dosed between 6/50 mg, 12/50 mg, and 18/50 mg (olanzapine/fluoxetine dose). Results from this study yielded a greater statistically significant reduction in mean total Montgomery Asberg Depression Rating Scale (MADRS) scores from baseline to endpoint for Symbyax versus fluoxetine and olanzapine alone.
A second study of 28 patients who met the same criteria for TRD demonstrated statistically significant greater reductions in MADRS scores for Symbyax versus fluoxetine and olanzapine alone.
A third study demonstrated statistically significant greater reductions in total MADRS scores for Symbyax versus fluoxetine or olanzapine alone, when analyzed in a subpopulation of depressed patients (n=251) who met the same criteria for treatment resistance.
Although not cited in the approved label, two additional studies were included in the sNDA data package. One of the trials provided statistically significant supporting data for Symbyax in the acute treatment of TRD, while the other trial was inconclusive.
An integrated analysis of all five studies provided to the FDA yielded a statistically significant greater reduction in mean total MADRS scores from baseline to endpoint in the defined population for patients treated with Symbyax (-12.2) vs. fluoxetine (-8.5, p=0.015) and olanzapine (-7.7, p=0.007) and greater statistically significant remission rates (p=<0.05) for patients treated with Symbyax (25.5 percent), vs. fluoxetine (17.3 percent) and olanzapine (14.0 percent).
Adverse events that were reported in five percent or more of Symbyax-treated patients in these trials and at twice the rate of placebo were weight gain, increased appetite, dry mouth, somnolence and fatigue. This is consistent with the current safety information provided in the Symbyax label.
Pivotal Studies for Bipolar Depression
Approval was based on the results of two identical, eight-week, randomized, double-blind, controlled studies of patients diagnosed with bipolar depression. Zyprexa and fluoxetine in combination (6/25, 6/50, or 12/50 mg/day respectively) were compared to both Zyprexa alone (5 to 20 mg/day) and placebo. The primary outcome was symptom improvement based on the Montgomery-Asberg Depression Rating Scale (MADRS). Both trials showed that combination therapy with Zyprexa and fluoxetine resulted in a statistically significant greater improvement compared to Zyprexa alone and placebo.
In one eight-week controlled trial, combination therapy with Zyprexa and fluoxetine (n=42) was superior to both
Zyprexa monotherapy (n=169) and placebo (n=174) in the reduction of the MADRS total score. -- In a second eight-week controlled trial, combination therapy with Zyprexa and fluoxetine (n=40) was superior to both Zyprexa monotherapy (n=182) and placebo (n=181) in the reduction of MADRS total score. About Treatment-Resistant Depression
It is estimated that up to 35 percent of patients with depression - or approximately two percent of the general population - fail to achieve an adequate response to two respective antidepressant drug therapy attempts. The exact causes of depression and why some people do not respond to initial pharmacological therapy is not known.
About Bipolar Depression
Depressive episodes associated with bipolar I disorder (also known as bipolar depression) refers to the depressive phase of bipolar disorder, a complex mental illness characterized by debilitating swings in mood. The swings range from manic episodes, marked by abnormal euphoria, elation and irritability, to episodes of deep depression, marked by extreme sadness and difficulty functioning.
Safety Information for Symbyax and Concomitant Use of Zyprexa and Fluoxetine
Symbyax is indicated in the United States for the acute treatment of bipolar depression and treatment-resistant depression in adults. Treatment-resistant depression is defined as major depressive disorder in adults who do not respond to two separate trials of different antidepressants of adequate dose and duration in the current episode.
Antidepressants can increase suicidal thoughts and behaviors in children, teens and young adults. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for worsening depression symptoms, unusual changes in behavior or thoughts of suicide. Patients and caregivers should be especially observant within the first few months of treatment or after a change in dose. Symbyax is not approved for children and adolescents.
Symbyax is not approved for the treatment of patients with dementia-related psychosis. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
In addition, compared to elderly patients with dementia-related psychosis taking a placebo, there was a significantly higher incidence of cerebrovascular adverse events in elderly patients with dementia-related psychosis treated with olanzapine, a component of Symbyax.
Symbyax should not be used with a monoamine oxidase inhibitor (MAOI) or within at least 14 days of discontinuing an MAOI. At least five weeks should be allowed after stopping Symbyax before starting an MAOI. Thioridazine should not be given with Symbyax or within at least five weeks after stopping Symbyax. Concomitant use of Symbyax in patients taking pimozide is contraindicated. Symbyax is contraindicated in patients with known hypersensitivity to the product or any component of the product.